FTD-TPI, Bevacizumab, and Radioembolization With 166Ho-microspheres in Refractory Metastatic Colorectal Cancer (STARLIGHT)

Single-arm, Phase II Trial of Trifluridine/Tipiracil (FTD-TPI), Bevacizumab, and Individualized Radioembolization With 166Ho-microspheres in Refractory Metastatic Colorectal Cancer

Extrahepatic disease progression limits clinical efficacy of individualized radioembolization for patients with refractory metastatic colorectal cancer (mCRC). In the same patient population, trifluridine/tipiracil (FTD-TPI) and bevacizumab lead to disease control and overall survival benefit and may be a radiosensitizer.

The purpose of this study is to determine safety, tolerability, and activity of individualized radioembolization with 166Holmium (166Ho)-microspheres combined with FTD-TPI and bevacizumab.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: Systemic treatment (FTD-TPI and bevacizumab); Device: Radioembolization with 166-Ho microspheres

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Guus Bol, dr.; Phone Number: +31 88 75 652 43; Email: G.M.Bol-2@umcutrecht.nl
• Study Contact Backup: Name: Dania Al-Toma, drs.; Email: D.Al-Toma-2@umcutrecht.nl

Study Locations

• Netherlands
  • Utrecht, Netherlands, 3584CX
    • Recruiting
    • UMC Utrecht
    • Contact: Guus Bol, dr.
    • Principal Investigator: Guus Bol, dr.
    • Sub-Investigator: Marnix Lam, dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Unresectable liver dominant mCRC

• Prior therapy with fluoropyrimidine, oxaliplatin, and irinotecan for the treatment of metastatic colorectal cancer and had demonstrated progressive disease or intolerance to their last regimen

  • Patients who have withdrawn from standard treatment due to unacceptable toxicity warranting discontinuation of treatment and precluding retreatment with the same agent prior to progression of disease will also be eligible to enter the study.
  • Patients who refuse oxaliplatin or irinotecan will also be eligible to enter the study.
  • Patients who had received adjuvant chemotherapy and had recurrence during or within 6 months of completion of the adjuvant chemotherapy count the adjuvant therapy as treatment of metastatic colorectal cancer.
• Written informed consent
• Age >=18 years
• Estimated hepatic tumor replacement ≥ 10% and ≤ 50% of total liver volume Eastern Cooperative Oncology Group performance status 0-1
• Adequate organ function as measured by: WBC ≥ 3.0 x 109/L, platelets ≥ 100 x 109/L, absolute neutrophil count > 1.5 x 109/L, Hemoglobin (Hb) > 5 mmol/L (>8.1 g/dL), eGFR ≥ 35 ml/min, Serum transaminases (AST & ALT) ≤ 5 x upper limit of normal (ULN), Total bilirubin ≤ ULN, Albumin > 3 g/dL
• At least one measurable liver lesion according to the PERCIST 1.0

Exclusion Criteria:

• Significant extrahepatic disease, defined as symptomatic extrahepatic disease, more than 10 pulmonary nodules (maximum diameter of each lung metastasis <20mm), and/or peritoneal carcinomatosis.
• Eligible for ablative local treatment of liver metastases (e.g. surgical resection, ablation)
• Lung shunt >20 Gy, as calculated using scout dose SPECT/CT
• Absorbed tumor dose <90 Gy when dosing at a maximum average absorbed normal liver dose
• Other malignancy confounding prognosis
• Receipt of chemotherapy within 28 days prior to study treatment
• Previous or current treatment with radioembolization
• Major surgery within 28 days or incompletely healed surgical incision before starting study therapy
• Any serious comorbidity preventing the safe administration of anti-VEGF antibody treatment. This includes uncontrolled hypertension or treatment with ≥3 antihypertensive drugs, arterial (cerebro)vascular event within the past 6 months, history of severe bleeding, history of GI perforation, or presence of fistulae
• Any serious and/or chronic liver disease preventing the safe administration of radio- embolization
• Uncorrectable extrahepatic deposition of scout dose activity; activity in the falciform ligament, portal lymph nodes and gallbladder is accepted
• Pregnancy or breastfeeding
• Body weight over 150 kg (because of maximum table load)
• Known severe allergy for intravenous contrast fluids
• Participation to another investigational study which may compromise any endpoint of the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Intervention: Systemic treatment (FTD-TPI + bevacizumab) and radioembolization; Individualized dose 166Ho radioembolization, combined with systemic treatment:; 35 mg/m2 FTD-TPI on day 1-5 and 8-12 every 4 weeks; 5 mg/kg bevacizumab iv. on day 1 and 15 every 4 weeks

Drug: Systemic treatment (FTD-TPI and bevacizumab); Systemic treatment (FTD-TPI and bevacizumab) administration is according to standard clinical practice. Each treatment cycle will be 28 days in duration. One treatment cycle consists of the following: Days 1-5: oral intake of FTD-TPI and bevacizumab IV infusion on day 1; Days 8-12: oral intake of FTD-TPI; Day 15: bevacizumab IV infusion Bevacizumab 5.0mg/kg i.v. is repeated every 2 weeks. If toxicity occurs, dose modifications and dose delays should be administered and applied according to standard practice.; Device: Radioembolization with 166-Ho microspheres; Individualized 166Ho radioembolization will be performed via a catheter during angiography. Before the treatment, a scout procedure will be performed to determine individualized 166Ho dose of the treatment. Dosimetry-based treatment planning will be individualized using Q- Suite software. In case of bilateral disease, patients will be treated in two procedures to each hemi-liver, separated by 1 month. Before the first procedure, a scout procedure will be performed in which the individualized 166Ho dose of the first and second procedure will be calculated.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hepatic objective response rate (hORR) (PERCIST 1.0)	Hepatic objective response rate (hORR) will be assessed by Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) 1.0.	Evaluated every 8 weeks after the start of treatment until 1 year after the start of treatment or until disease progression, whichever comes first.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hepatic objective response rate (hORR) (RECIST 1.1)	Hepatic objective response rate (hORR) will be assessed by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1.	Evaluated every 8 weeks after the start of treatment until 1 year after the start of treatment or until disease progression, whichever comes first.
Overall and extra-hepatic ORR (RECIST 1.1)	Overall and extra-hepatic ORR will be assessed by RECIST 1.1.	Evaluated every 8 weeks after the start of treatment until 1 year after the start of treatment or until disease progression, whichever comes first.
Overall and extra-hepatic ORR (PERCIST 1.0)	Overall and extra-hepatic ORR will be assessed by PERCIST 1.0.	Evaluated every 8 weeks after the start of treatment until 1 year after the start of treatment or until disease progression, whichever comes first.
Serious adverse events (SAE's)	The occurrence of any (suspected unexpected) serious adverse event (SAE) that is possibly, probably or definitely related to the combined treatment.	Evaluated every 8 weeks after start treatment during the first half year. The collection period will start from the first day of the first treatment cycle until 180 days thereafter.
Grade ≥3 adverse events (CTCAE 5.0)	The rate of grade ≥3 adverse events (CTCAE 5.0).	Evaluated every 8 weeks after start treatment during the first half year. The collection period will start from the first day of the first treatment cycle until 180 days thereafter.
Occurrence of radioembolization-induced liver disease (REILD)	Radioembolization-induced liver disease (REILD) is defined as a total bilirubin increase to grade ≥3 or higher according to the CTCAE v5.0, in combination with ascites and low albumin, developing at least 2 weeks after radioembolization and up to 4 months after radioembolization, in the absence of tumor progression or biliary obstruction.	Evaluated every 8 weeks after start treatment during the first half year.
Radioembolization related vascular events	Number of participants with a vascular event (dissection, pseudo-aneurism, thrombus etc.) that is possibly, probably or definitely related to the radioembolization.	Evaluated every 8 weeks after start treatment during the first half year.
Dose reductions, dose delays of FTD-TPI	The frequency of dose reductions and dose delays of FTD-TPI during the first 2 cycles.	Evaluated during the first two cycles (each cycle is 28 days).
Radioembolization completion rate	Defined as the successful treatment of both hemi-livers (in case of bilateral disease) according to the individualized treatment plan designed at the scout dose.	Evaluated immediately after the radioembolization treatment.
Progression free survival (PFS)	PFS is defined as time from the first day of the first treatment cycle to progression of disease or death, whichever occurs first. Progression of disease is based on tumor response as observed on radiographic imaging according to RECIST 1.1.	Evaluated every 8 weeks after the start of treatment until 1 year after the start of treatment or until disease progression, whichever comes first.
Overall survival (OS)	OS is defined as the time from the first day of the first treatment cycle to the date of death. Patients still alive at the analysis cut-off date are censored at the last date known to be alive. OS will be collected for all patients from the Personal Records Database (BRP), yearly during the duration of the study.	Evaluated once per year until the end of the study (the end of study is defined as six months after the first day of the first treatment cycle (each cycle is 28 days) of the 36th evaluable participant).

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dosimetry scout + post treatment 1 and 2	To evaluate biodistribution / dosimetry using CT and quantitative SPECT both for scout dose imaging and post-treatment imaging. Tumor dose and normal liver dose will be calculated for each hemi-liver in the scout procedure and two post treatment scans.	Evaluated immediately after the radioembolization treatment.

Collaborators and Investigators

• Sponsor: UMC Utrecht

Study record dates

Study Major Dates

• Study Start (Actual): June 18, 2024
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: June 7, 2024
• First Submitted That Met QC Criteria: August 20, 2024
• First Posted (Actual): August 21, 2024

Study Record Updates

• Last Update Posted (Actual): August 21, 2024
• Last Update Submitted That Met QC Criteria: August 20, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Radioembolization; Trifluridine/Tipiracil; Refractory Metastatic Colorectal Cancer; Radioembolization With 166Ho-microspheres
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab
• Other Study ID Numbers: NL85987.041.24

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No